Cigarette smoke and smokeless tobacco contains many carcinogens, mutagens and teratogens. Among them the tobacco specific nitrosamine call NNK 4- (N-Methyl-N-nitrosamine)-l-(3-pyridyl)-l-butanone) is a potent carcinogen which was found to induce tumors primarily of the respiratory tract in laboratory animals. in our preliminary studies it was observed that NNK treatment inhibited antibody responses and lymphocyte proliferation from the regional pulmonary lymphoid tissues. Also there was severe atrophy of the thymus in NNK treated mice compared to control mice. In the present study we propose to investigate the magnitude and kinetics of organ specific immunosuppression by treating mice with different doses of NNK. Also experiments will be conducted to determine the cellular basis of this immunosuppression. Is it due to changes in the frequency of lymphocyte subsets, or suppression of lymphokine levels secreted by T cells and/or changes in the function of antigen presenting cells in the lung and lung associated hilar lymph nodes of NNK treated mice. Next experiments will be conducted to determine whether NNK treatment affects host anti tumor immune mechanism involving natural killer cells, lymphokine activated killer cells or cytotoxic T cells. Finally, studies also will be conducted to determine the degree of thymic atrophy induced by different doses of NNK treatment and the alterations in the proportion of different thymocyte subsets and test whether apoptosis is responsible for thymic atrophy. Results obtained from this study might help us in understanding why human smokers are more susceptible to respiratory diseases and cancer.